latent tuberculosis recent advances srms

latent tuberculosis recent advances

1. Latent TB ( Recent advances) DR ASIF FEROZ JR1 MODERATOR: DR RAJEEV TANDON

2. BURDEN TB infection: A persistent state of immunological response to stimulation by M. tuberculosis antigens without any evidence of clinically manifest tuberculosis disease. As per national tuberculosis prevalence survey (2015- 2021) prevalence of TB infection in India among adults (> 15 years) is 31.3% (crude prevalence; basis: IGRA) More recent meta- analysis has detected the prevalence to be 3 6 % in general population (excluding high risk groups) and 40% in the population with high- risk groups included

3. Latent tuberculosis infection(LTBI) The World Health Organization (WHO) defines LTBI as a state of sustained immune response to previously acquired Mycobacterium tuberculosis antigens with no evidence of active tuberculosis and no clinical manifestations. The US Centers for Disease Control and Prevention defines LTBI as a person who is infected with Mycobacterium tuberculosis but has no clinical signs or symptoms of active tuberculosis.

4. RISK OF TB DISEASE Generally, 5- 15% of subjects with TB infection develops TB disease in their lifetime Highest risk of contracting infection is house- hold/close contact with active pulmonary TB patients Globally, people with certain ailments are at a higher risk of TBI progression to active disease Children < 5 years are most vulnerable amongst all groups

5. HOUSEHOLD AND CLOSE CONTACTS Close contacts: A person who is not in the household but S hared an enclosed space, such as at a social gathering, workplace or facility F or extended periods during the day with the index TB patient D uring the three months before commencement of the current TB treatment episode. House- hold contacts A person who S hared the same enclosed living space as the index TB patient F or one or more nights or for frequent or extended daytime periods D uring the three months before the start of current TB treatment.

6. Natural history of TB and progression of TB to LTBI

7. Mechanism Latent bacilli remain dormant within early lesions within the upper lobes of the lung. Individuals with LTBI kept them for the rest of their lives. Reactivation of dormant bacilli - TB develops . Furthermore, the pressure within the upper lobes increases, promoting bacillary multiplication and lessening immunological responses. The disease develops when a person breathes tubercle bacilli-containing droplet nuclei that reach the lung alveoli. Alveolar macrophages consume these tubercle bacilli; most bacilli are killed or inhibited.

8. A small percentage of the dead macrophages may multiply intracellularly and eject themselves. If these bacteria are alive and well, they might spread to other tissues and organs via the lymphatic or circulatory systems (including areas where TB disease is most likely to develop apex of the lung, kidneys, bone, regional lymph nodes, and brain) .

9. SCREENING OF LTBI Screening is essential for initiating treatment. The decision for treatment is made after TB screening. Individuals at risk of getting mycobacterium tuberculosis and progression from LTBI to active TB is benefitted from screening. The targeted Mantoux tuberculin skin test (TST) is the most extensively used tool for LTBI screening .

10. Recommendations for Testing of LTBI The gold standard for diagnosing active infection is bacterial culture , but there is no equivalent standard for detecting LTBI . Diagnosis of LTBI includes either an interferon-gamma release assay (IGRA) or a TST . According to the WHO post-2015 End TB Strategies recommendation for the management of LTBI for higher/upper middle-income countries with TB incidence of less than 100/100,000 individuals , systematic testing and treatment for LTBI is strongly recommended.

11. Method for testing for LTBI (modified from WHO and CDC guidelines). In India, the TST may be chosen over the IGRA.

12. New LTBI Diagnostics Due to the deficit of the accepted gold standard for diagnosing LTBI, there may be problems with outcome classification . The Cy-Tb testing is one of the most recent advancements, which employs M antigens that are unique to TB, like those used in IGRAs, which maintain the sensitivity of the current TST assay while removing cross-reactivity with the Bacille Calmette- Guérin vaccination .

13. The world has just launched a new version of the QuantiFERON test. New antigens have been incorporated into the QuantiFERON-TB Gold Plus assay to improve test sensitivity in immunocompromised populations, including HIV-positive individuals. IGRA and the TST cannot reliably differentiate between active TB disease and LTBI, nor can they predict LTBI reactivation

14. Tuberculin skin test The TST is a traditional diagnostic method based on the principle of a type IV allergic reaction. It is an in vivo skin test that uses pure protein derivatives of tuberculin to induce a hypersensitivity reaction. By injecting tuberculin into the subcutaneous and observing whether the injection site produces a red and swollen reaction.

15. Th e criteria for determining LTBI are: those with an average diameter of hard nodules <5mm or no reaction are negative; b) those with an average diameter of hard nodules ≥5mm are positive c) those with an average diameter of hard nodules 5–10mm are generally positive; d) those with an average diameter of hard nodules 10–15mm are moderately positive e) those with an average diameter of hard nodules ≥15mm or with the presence of localized double circles, blisters, necrosis and lymphangitis are strongly positive .

16. Interferon-Gamma Release Assay (IGRA) The IGRA is an in vitro assay that determines the presence of a bacterial infection based on the host immune response to specific antigens of MTB. A chieved by measuring the level of gamma-interferon (IFN- γ) released by activated T-lymphocytes.

17.   IGRA is comprised of two principal assays: enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunospot assay (ELISPOT), both employ early secretory antigen target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) as specific antigens .

18. Molecular Biology Testing Techinques RNA SEQUENCING In recent years, RNA sequencing has been increasingly employed for the diagnosis of latent infections, particularly in the context of long-stranded non-coding RNA ( lncRNA ) expression profiling.  By analyzing exosomal RNA expression patterns in blood, molecular markers associated with latent infection can be identified.  Furthermore, the presence of LTBI can be discerned through the identification of specific microRNAs in serum

19. Proteomics The application of proteomics technology offers a novel methodology for the diagnosis of LTBI. This approach involves the detection and identification of proteins and their interactions that are closely associated with the development of disease. The prolonged carriage of pathogens in individuals with latent infection may result in alterations to the expression of associated proteins .

20. These altered proteins may serve as potential biomarkers for diagnosis and differential diagnosis. It was observed that α-1- antitrypsin, α-1- acid glycoprotein 1, and E- calcimucil exhibited greater capacity to differentiate between patients with ATB and those with LTBI.

21. Advances in biomarker cytokine research MTB stimulates macrophages to produce cytokines, which are associated with the activation and differentiation of T lymphocytes and mediate the immune response. The main cytokines identified thus far are interferons (IFNs), interleukins (ILs), tumor necrosis factors (TNFs), and chemokines.

22. The most prevalent investigations focusing on IFN- γ, IL-6, IL-4, IL-2, and other related cytokines. IL is an important factor regulating the immune system, affecting the progression of LTBI by regulating immune responses and cellular functions and its mechanisms in immune evasion are mainly immunosuppressive cytokines, regulatory T cells, etc. The role of IFNs in promoting the development of LTBI is mainly manifested in their regulation of the immune system and the ability to pathogen inhibitory ability to achieve immune evasion through inhibition of interferon signaling and alteration of host cell phenotype.

23. Key Cytokines in LTBI Diagnosis 🔹 Interferon-Gamma (IFN- γ) Role : Central to IGRA (Interferon-Gamma Release Assays), which are widely used for LTBI screening. Findings : Elevated in TB > LTBI > healthy controls. Not sufficient alone to distinguish LTBI from active TB (ATB). Limitations : IFN- γ levels can be influenced by HIV, diabetes, age, and immune status. Best used in combination with IL-2 for improved specifici

24. 🔹 Interleukin-2 (IL-2) Role : Stimulates T-cell proliferation and immune memory. Findings : Elevated in LTBI vs. healthy controls. IL-2 release assays show high sensitivity (90%) and specificity (97.5%) for LTBI. Strengths : IL-2 + IFN- γ combination enhances diagnostic accuracy. Useful for staging disease and predicting reactivation risk.

25. 🔹 Interleukin-6 (IL-6) Role : Pro-inflammatory cytokine involved in acute phase response. Findings : Highest in TB, moderate in LTBI, lowest in healthy controls. Strongly associated with disease progression. Limitations : Overlapping levels across groups; best used in multiplex panels.

26. 🔹 Interleukin-4 (IL-4) • Role : Th2-type cytokine involved in humoral immunity. • Findings: • Lower in LTBI than in TB and healthy controls. • Pattern differs from IL-6 and IFN-γ. • Uncertainty: • Conflicting data; not yet a reliable standalone marker

27. ROLE OF PREVENTIVE THERAPY Effectiveness was greater in TST/IGRA positive children (AHR- 0.05 vs 0.GG) BCG vaccination protective against all forms of TB in < 5 years children No protective effect of BCG vaccination in children above 5 years

28. GUIDELINES: WHO TO TREAT?

29. TREATMENT OPTIONS Isoniazid for 6 months (for all ages, in both high and low prevalence countries) Rifampicin + is oniazid for 3 months (< 15 years of age, in high prevalence studies) Rifapentin+Isoniazid weekly for 3 months (for high prevalence countries)

30. REGIMENS RECOMMENDED IN INDIA

31. Treatment The long-term reduction of the TB burden can be achieved in two ways. One strategy calls for the prompt and early detection of all individuals having active TB and the implementation of appropriate treatment. An alternative strategy is to identify those still suffering from LTBI and treat them to stop the later onset of the disease.

32. Drug dosage recommendation for LTBI treatment

33. MANAGEMENT OF CONTACTS OF DR- TB Levofloxacin for 6 months: for Rif- resistant Rifampicin for 4 months: for H- mono/poly

34. REGIMENS

35. ADVERSE EVENTS AND HOW TO MANAGE

36. CONCLUSIONS & CONCERNS 3HP regimen has fewer rate of side effects The deaths in 3HP group (or any group) were not attributed to the drugs The higher rates of deaths were observed in patients with advanced HIV infection or other underlying diseases Very few studies reported flu- like symptoms or other side effects (indicating they were not very common); There was almost no case of hypersensitivity and angio- oedema in any of the studies

37. LACUNAE: WHAT MIGHT IMPROVE COVERAGE? Larger studies examining the safety of TPT in general population and among special groups Larger studies to examine emergence of drug resistance among recipients of TPT RCTs evaluating shorter and safer regimens

38. Recruitment of sufficient lab technicians and health- care- workers for implementation of policy Better IEC activity regarding the benefits of TPT and the incentives offered

39. CONCLUSIONS The chance of development of active TB from TB infection is substantial and may add to burden of TB treatment cost Certain populations are at a higher risk TB preventive treatment has proven effective against preventing development of active TB in infected individuals TB preventive therapy is largely safe, and the side effects are easily manageable

40. For drug resistant TB contacts, the knowledge of resistance patterns of the index patient is important Upcoming researches may unfold shorter regimens with better adherence and lesser side effects

41. Thank you